Extracorporeal Circulation (ECC) is essential to modern medicine ( heart surgery, hemodialysis, plasmapheresis, life support in intensive care).Systemic anticoagulation is required for ECC, but it is the major cause of complications and the limiting factor to the technology. Despite solid understanding of the mechanisms of blood-surface interaction, and despite decades of bioengineering research, the non-thrombogenic prosthetic surface remains an unsolved problem. The problems of thrombosis and anticoagulation are magnified during prolonged ECC. During the past 30 years we have developed prolonged ECC (ECLS, ECMO) from bench to animal testing to routine clinical application. Our current grant (and the proposed renewal) is focused on the last major issue limiting prolonged ECC: thrombosis and anticoagulation. Surfaces which prevent fibrin formation (heparin, albumin, and hydrophilic surfaces) still require systemic anticoagulation, unmasking the fact that the basic problem is the platelet. We believe we can now solve this problem by developing a surface that prevents platelet adhesion and activation by continuously generating nitric oxide. In the past three years we have characterized NO releasing surfaces, demonstrating prevention of thrombosis without anticoagulation. We have used that information to create a surface which continuously generates NO from nitrosothiols in the circulating blood. The safety and efficacy of these two approaches has been demonstrated in the rabbit model. We now propose to optimize the NO releasing surface in the clinically relevant sheep model while further refining the NO generating surface in the rabbit. Then we will define the best approach in the acute and chronic sheep, leading to clinical trials. The results will apply to all blood surface interactions including short term ECC, intravascular, and implantable devices. PUBLIC HEALTH RELEVANCE: Circulation of blood through artificial organs is essential to modern medicine (heart surgery, dialysis for kidney failure, life support in intensive care), but anticoagulant drugs are required to prevent clotting in the device, often leading to bleeding in the patient. The goal of this research is to develop and test a plastic surface for extracorporeal circulation that prevents clotting (is nonthrombogenic ), so that anticoagulation can be eliminated. We make plastic which produces a chemical called nitric oxide (like the blood vessels), which prevents clotting on the surface.